Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells

J Immunol. 2015 Aug 1;195(3):1202-17. doi: 10.4049/jimmunol.1403013. Epub 2015 Jun 24.

Abstract

Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is essential for immunity to infection. CRAC channels are formed by ORAI1 proteins in the plasma membrane and activated by stromal interaction molecule (STIM)1 and STIM2 in the endoplasmic reticulum. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause severe immunodeficiency with recurrent infections due to impaired T cell function. SOCE has also been observed in cells of the innate immune system such as macrophages and dendritic cells (DCs) and may provide Ca(2+) signals required for their function. The specific role of SOCE in macrophage and DC function, as well as its contribution to innate immunity, however, is not well defined. We found that nonselective inhibition of Ca(2+) signaling strongly impairs many effector functions of bone marrow-derived macrophages and bone marrow-derived DCs, including phagocytosis, inflammasome activation, and priming of T cells. Surprisingly, however, macrophages and DCs from mice with conditional deletion of Stim1 and Stim2 genes, and therefore complete inhibition of SOCE, showed no major functional defects. Their differentiation, FcR-dependent and -independent phagocytosis, phagolysosome fusion, cytokine production, NLRP3 inflammasome activation, and their ability to present Ags to activate T cells were preserved. Our findings demonstrate that STIM1, STIM2, and SOCE are dispensable for many critical effector functions of macrophages and DCs, which has important implications for CRAC channel inhibition as a therapeutic strategy to suppress pathogenic T cells while not interfering with myeloid cell functions required for innate immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • Apoptosis Regulatory Proteins / immunology
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling / immunology*
  • Calcium-Binding Proteins / immunology
  • Carrier Proteins / immunology
  • Cell Differentiation / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Immunity, Innate / immunology
  • Inflammasomes / immunology
  • Lymphocyte Activation / immunology
  • Macrophages / cytology
  • Macrophages / immunology*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • ORAI1 Protein
  • Phagocytosis / immunology
  • Severe Combined Immunodeficiency / genetics
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • T-Lymphocytes / immunology

Substances

  • Apoptosis Regulatory Proteins
  • Calcium Channels
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Inflammasomes
  • Ipaf protein, mouse
  • Membrane Glycoproteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • ORAI1 Protein
  • Orai1 protein, mouse
  • Stim1 protein, mouse
  • Stim2 protein, mouse
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • Calcium